The present invention relates to novel thienopyridines, to methods for their preparation, to compositions comprising the compounds, to the use of these compounds as medicaments and their use in therapy, where such compounds of Formula 1 are pharmacologically useful inhibitors or modulators of Protein Tyrosine Phosphatases (PTPases) including PTP1B and T cell PTP, 
wherein X, R1, R2, R3, and R4 are defined more fully below.
It has been found that PTPases play a major role in the modulation and regulation of fundamental cellular signaling mechanisms involved in metabolism, growth, proliferation and differentiation (Fischer et al, Science 253:401-6 (1991); Tonks and Neel, Cell 87: 365-368 (1996); Neel and Tonks, Current Opinion in Cell Biology 9: 193-204 (1997); Hunter, Phil. Trans. R. Soc. Lond. B 353: 583-605 (1998); Zhang, Critical Reviews in Biochemistry and Molecular Biology 33:1-52 (1998)). There is increasing evidence which suggests that inhibition of these PTPases may help treat or manage certain types of diseases such as type 1 and type 2 diabetes, obesity, autoimmune diseases, acute and chronic inflammation, osteoporosis and various forms of cancer. In addition, certain infectious diseases may also be treated or managed by administration PTPase inhibitors (Clemens et al., Molecular Microbiology 5: 2617-2620 (1991)).
Protein phosphorylation is now well recognized as an important mechanism utilized by cells to transduce and regulate signals during different stages of cellular function (Hunter, vide supra; Chan et al., Annu. Rev. Immunol. 12: 555-592 (1994); Zhang, Curr. Top. Cell. Reg. 35: 21-68 (1997); Matozaki and Kasuga, Cell. Signal. 8: 113-19 (1996); Fischer et al, vide supra). The level of tyrosine phosphorylation is balanced by the opposing action of protein tyrosine kinases and protein tyrosine phosphatases (PTPases). There are at least two major classes of phosphatases: (1) those that dephosphorylate proteins (or peptides) that contain a phosphate group(s) on a serine or threonine moiety (termed Ser/Thr phosphatases) and (2) those that remove a phosphate group(s) from the amino acid tyrosine (termed protein tyrosine phosphatases or PTPases or PTPs). The PTPases are a family of enzymes that can be classified into two groups: a) intracellular or nontransmembrane PTPases and b) receptor-type or transmembrane PTPases. In addition, dual-specificity phosphatases and low molecular weight phosphatases can also dephosphorylate phosphotyrosyl proteins (WO97/39748, WO97/40017, WO99/15529, WO97/08934, WO98/27065, WO99/46236, WO99/46244, WO99/46267, WO99/46268, WO99/46237).
It has been found that PTPases play a major role in the above modulation and regulation of fundamental cellular signaling mechanisms involved in metabolism, growth, proliferation and differentiation (Fischer et al, Science 253:401-6 (1991); Tonks and Neel, Cell 87: 365-368 (1996); Neel and Tonks, Current Opinion in Cell Biology 9: 193-204 (1997); Hunter, Phil. Trans. R. Soc. Lond. B 353: 583-605 (1998); Zhang, Critical Reviews in Biochemistry and Molecular Biology 33:1-52 (1998)). Reports from many laboratories have shown that PTPases can act both as positive and negative regulators of signal transduction processes. PTPases have been implicated in a variety of human diseases, including type land type diabetes, obesity, autoimmune diseases, acute and chronic inflammation, osteoporosis, proliferative disorders including various forms of cancer, growth disorders, and defective platelet aggregation (WO97/39748, WO97/40017, WO99115529, WO97/08934, WO98/27065, WO99/46236, WO99/46244, WO99/46267, WO99/46268, WO99/46237). Accordingly, there is increasing evidence which suggests that inhibition of these PTPases may help treat or manage said diseases (Hunter, vide supra; Neel and Tonks, vide supra; Frangione et al., EMBO J. 12: 4843-4856; Zhang, Curr. Top. Cell. Reg. 35: 21-68 (1997); Zhang, vide supra; Evans and Jallan, Exp. Opinion. Invest. Drugs 8: 139-160 (1999); Burke and Zhang, Biopolymers (Peptide Science) 47: 225-241 (1998); Elchebly et al., Science 283: 1544-1548 (1999); Wrobel et al., J. Med. Chem. 42: 3199-3202 (1999)). In addition, certain infectious diseases may also be treated or managed by administration PTPase inhibitors (Clemens et al., Molecular Microbiology 5: 2617-2620 (1991)).
Both selective PTPase inhibitors and inhibitors that bind to several PTPases (non-selective inhibitors) can be used therapeutically to partially or completely restore PTPase-mediated perturbed signal transduction processes and thus for management, treatment or prevention of the above diseases.
WO 99/46267 discloses compounds which are pharmacologically useful inhibitors of PTPases. However, the present invention which represents a novel selection under WO 99/46267, discloses a class of compounds which surprisingly are more potent against protein tyrosine phosphatases (e.g. PTP1 B) than those disclosed in WO 99/46267.
The present invention relates to compounds of the Formula 1 wherein X, R1, R2, R3, and R4 are defined below; 
wherein
X is xe2x80x94C(O)xe2x80x94 or xe2x80x94S(O)2xe2x80x94;
R1 and R2 are independently hydrogen, C1-C6alkyl, aryl-R5xe2x80x94, R6xe2x80x94C(O)xe2x80x94Oxe2x80x94R7xe2x80x94 or aryl-R8xe2x80x94C(O)xe2x80x94Oxe2x80x94R9xe2x80x94 wherein aryl is phenyl, naphthyl or thiophenyl, which aryl group is optionally substituted with halogen, nitro, trihalomethyl, C1-C6alkyl or C1-C6alkyloxy;
R3 is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, aryl, aryl-R10xe2x80x94, aryl-N(R35)xe2x80x94, aryl-R11xe2x80x94N(R36)xe2x80x94, N(R37)(R38)xe2x80x94R39xe2x80x94, C1-C6alkyloxy or aryl-R13xe2x80x94Oxe2x80x94 wherein aryl is phenyl, biphenyl, indenyl, naphthyl, imidazolyl, benzo[b]furanyl, 1,2,3-triazolyl, thiophenyl, pyridyl, quinolyl, isoquinolyl, indolyl or benzimidazolyl, which aryl group is optionally substituted with halogen, nitro, cyano, hydroxy, trihalomethyl, C1-C6alkyl, aryl, aryl-R14xe2x80x94, C1-C6alkyloxy, aryloxy, aryl-R15xe2x80x94Oxe2x80x94, aryl-N(R16)xe2x80x94, R18xe2x80x94C(O)xe2x80x94N(R19)xe2x80x94, aryl-C(O)xe2x80x94N(R21)xe2x80x94 or aryl-R23xe2x80x94C(O)xe2x80x94N(R24)xe2x80x94 and wherein aryl is phenyl, naphthyl or thiophenyl;
R4 is hydrogen, R27xe2x80x94Oxe2x80x94C(O)xe2x80x94, aryl-R28xe2x80x94Oxe2x80x94C(O)xe2x80x94, R29xe2x80x94C(O)xe2x80x94Oxe2x80x94R30xe2x80x94OC(O)xe2x80x94 or aryl-R31xe2x80x94C(O)xe2x80x94Oxe2x80x94R32xe2x80x94Oxe2x80x94C(O)xe2x80x94 wherein aryl is phenyl, naphthyl or thiophenyl, which aryl group is optionally substituted with halogen, nitro, cyano, trihalomethyl, aryl, aryl-R33xe2x80x94, C1-C6alkyloxy or aryl-R34xe2x80x94Oxe2x80x94 and wherein aryl group is phenyl, naphthyl or thiophenyl;
and wherein R5, R7, R8, R9, R10, R11, R13, R14, R15, R23, R28, R30, R31, R32, R33, R34, and R39 independently are C1-C6alkylene, wherein R6, R12, R17, R18, R20, R22, R25, R27, R29, R37, and R38 independently are C1-C6alkyl and wherein R16, R19, R21, R24, R35 and R36 independently are hydrogen or C1-C6alkyl;
or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric form.
The compounds of the invention can be further modified to act as prodrugs.
A preferred prodrug is acetoxymethyl esters or acetoxymethyl carbamates of the compounds of the present invention. As a general procedure preparation of an acetoxymethyl ester is given below (C. Schultz et al, The Journal of Biological Chemistry, 1993, 268, 6316-6322.):
A carboxylic acid (1 equivalent) is suspended in dry acetonitrile (2 ml per 0.1 mmol). Diisopropyl amine (3.0 equivalents) is added followed by bromomethyl acetate (1.5 equivalents). The mixture is stirred under nitrogen overnight at room temperature. Acetonitrile is removed under reduced pressure to yield an oil which is diluted in ethyl acetate and washed with water (3xc3x97). The organic layer is dried over anhydrous magnesium sulfate, filtred and the solvent removal under reduced pressure affording a crude oil. The product is purified by column chromatography on silica gel, using an appropriate solvent system known to those skilled in the art.
As used herein, the term xe2x80x9cattachedxe2x80x9d or xe2x80x9cxe2x88x92xe2x80x9d signifies a stable covalent bond, certain preferred points of attachment points being apparent to those skilled in the art.
The terms xe2x80x9chalogenxe2x80x9d and xe2x80x9chaloxe2x80x9d includes fluorine, chlorine, bromine, and iodine.
The term xe2x80x9calkylxe2x80x9d includes C1-C6 straight chain saturated, C1-C6 branched chain saturated and C3-C6 cyclic saturated hydrocarbon groups. For example, this definition shall include but is not limited to methyl (Me), ethyl (Et), propyl (Pr), butyl (Bu), pentyl, hexyl, isopropyl (i-Pr), isobutyl (i-Bu), tert-butyl (t-Bu), sec-butyl (s-Bu), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
The term xe2x80x9calkenylxe2x80x9d includes C2-C6 unsaturated aliphatic hydrocarbon groups and C2-C6 branched unsaturated aliphatic hydrocarbon groups having the specified number of carbon atoms and at lest one double bond. For example, this definition shall include but is not limited to ethenyl, propenyl, butenyl, pentenyl, hexenyl, isopentenyl, neopentenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and the like.
The term xe2x80x9calkynylxe2x80x9d includes C2-C6 straight chain unsaturated aliphatic, C2-C6 branched unsaturated and cyclic C6 unsaturated aliphatic hydrocarbon groups having the specified number of carbon atoms and at least one triple bond. For example, this definition shall include but is not limited to acetynyl, propynyl, butynyl, pentynyl, hexynyl, cyclohexynyl and the like.
The term xe2x80x9calkyloxyxe2x80x9d (e.g. methoxy, ethoxy, propyloxy, allyloxy, cyclohexyloxy) represents an xe2x80x9calkylxe2x80x9d group as defined in claim 1 having the indicated number of carbon atoms attached through an oxygen bridge.
The term xe2x80x9caryloxyxe2x80x9d (e.g. phenoxy, naphthyloxy and the like) represents an aryl group as defined below attached through an oxygen bridge.
The term xe2x80x9carylxe2x80x9d represents an unsubstituted, mono-, di- or trisubstituted monocyclic, polycyclic, biaryl or heterocyclic aromatic group(s) covalently attached at any ring position capable of forming a stable covalent bond, certain preferred points of attachment being apparent to those skilled in the art (e.g., 3-indolyl, 4(5)-imidazolyl).
The definition of aryl includes phenyl, biphenyl, indenyl, naphthyl (1-naphthyl, 2-naphthyl), imidazolyl (1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), triazolyl (1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl 1,2,3-triazol-4-yl, 1,2,4-triazol-3-yl), thiophenyl (2-thiophenyl, 3-thiophenyl, 4-thiophenyl, 5-thiophenyl), pyridyl (2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl), quinolyl (2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl), isoquinolyl (1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl), indolyl (1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl), benzo[b]furanyl (2-benzo[b]furanyl, 3-benzo[b]furanyl, 4-benzo[b]furanyl, 5-benzo[b]furanyl, 6-benzo[b]furanyl, 7-benzo[b]furanyl), benzimidazolyl (1-benzimidazolyl, 2-benzimidazolyl, 4-benzimidazolyl, 5-benzimidazolyl, 6-benzimidazolyl, 7-benzimidazolyl, 8-benzimidazolyl).
It is a well known problem in drug discovery that compounds, such as enzyme inhibitors, may be very potent and selective in biochemical assays, yet be inactive in vivo. This lack of so-called bioavailability may be ascribed to a number of different factors such as lack of or poor absorption in the gut, first pass metabolism in the liver, poor uptake in cells. Although the factors determining bioavailability are not completely understood, there are many examples in the scientific literaturexe2x80x94well known to those skilled in the artxe2x80x94of how to modify compounds, which are potent and selective in biochemical assays but show low or no activity in vivo, into drugs that are biologically active. By the term xe2x80x98original compoundxe2x80x99 is understood a compound of Formula I wherein R1 and R2 are both hydrogen. It is within the scope of the invention to modify the original compounds of the invention by attaching chemical groups that will improve the bioavailability of said compounds in such a way that the uptake in cells or mammals is facilitated. Examples of said modifications, which are not intended in any way to limit the scope of the invention, include changing of one or more of the carboxy groups at the R1 and R2 position to esters (for instance methyl esters, ethyl esters, acetoxymethyl esters or other acyloxymethyl esters). Original compounds of the invention modified by attaching chemical groups are termed xe2x80x98modified compoundsxe2x80x99. Other examples of modified compounds, which are not intended in any way to limit the scope of the invention, are compounds that have been cyclized at specific positionsxe2x80x94so called xe2x80x98cyclic compoundsxe2x80x99xe2x80x94which upon uptake in cells or mammals become hydrolysed at the same specific position(s) in the molecule to yield the compounds of the invention, the original compounds, which are then said to be xe2x80x98non-cyclicxe2x80x99. For the avoidance of doubt, it is understood that the latter original compounds in most cases will contain other cyclic or heterocyclic structures that will not be hydrolysed after uptake in cells or mammals. Generally, said modified compounds may not show behaviour in biochemical assays similar to that of the original compound, i.e. the corresponding compounds of the invention without the attached chemical groups or said modifications. Said modified compounds may even be inactive in biochemical assays. However, after uptake in cells or mammals these attached chemical groups of the modified compounds may in turn be removed spontaneously or by endogenous enzymes or enzyme systems to yield compounds of the invention, original compounds. xe2x80x98Uptakexe2x80x99 is defined as any process that will lead to a substantial concentration of the compound inside cells or in mammals. After uptake in cells or mammals and after removal of said attached chemical group or hydrolysis of said cyclic compound, the compounds may have the same structure as the original compounds and thereby regain their activity and hence become active in cells and/or in vivo after uptake. Thus, the term xe2x80x98a functional group which can be converted to hydrogen in vivoxe2x80x99 is intended to include any group which upon administering the present compounds to the subjects in need thereof can be converted to hydrogen e.g. enzymatically or by the acidic environment in the stomach.
The compounds of the present invention have asymmetric centers and may occur as racemates, racemic mixtures, and as individual enantiomers or diastereoisomers, with all isomeric forms being included in the present invention as well as mixtures thereof.
Pharmaceutically acceptable salts of the compounds of Formula 1, where a basic or acidic group is present in the structure, are also included within the scope of this invention. When an acidic substituent is present, such as xe2x80x94COOH, 5-tetrazolyl or xe2x80x94P(O)(OH)2, there can be formed the ammonium, morpholinium, sodium, potassium, barium, calcium salt, and the like, for use as the dosage form. When a basic group is present, such as amino or a basic heteroaryl radical, such as pyridyl, an acidic salt, such as hydrochloride, hydrobromide, phosphate, sulfate, trifluoroacetate, trichloroacetate, acetate, oxalate, maleate, pyruvate, malonate, succinate, citrate, tartarate, fumarate, mandelate, benzoate, cinnamate, methanesulfonate, ethane sulfonate, picrate and the like, and include acids related to the pharmaceutically acceptable salts listed in Journal of Pharmaceutical Science, 66, 2 (1977) and incorporated herein by reference, can be used as the dosage form.
Also, in the case of the xe2x80x94COOH or xe2x80x94P(O)(OH)2 being present, pharmaceutically acceptable esters can be employed, e.g., methyl, tert-butyl, pivaloyloxymethyl, and the like, and those esters known in the art for modifying solubility or hydrolysis characteristics for use as sustained release or prodrug formulations. In addition, some of the compounds of the present invention may form solvates with water or common organic solvents. Such solvates are encompassed within the scope of the invention.
The term xe2x80x9ctherapeutically effective amountxe2x80x9d shall mean that amount of drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal, or human that is being sought by a researcher, veterinarian, medical doctor or other.
In a preferred embodiment, the present invention is concerned with compounds of Formula 1
wherein
X is xe2x80x94C(O)xe2x80x94 or xe2x80x94S(O)2xe2x80x94;
R1 and R2 are independently hydrogen or a functional group that can be converted to hydrogen in vivo;
R3 is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, aryl, aryl-R10xe2x80x94, aryl-N(R35)xe2x80x94, aryl-R11xe2x80x94N(R36)xe2x80x94, N(R37)(R38)xe2x80x94R39xe2x80x94, C1-C6alkyloxy or aryl-R13xe2x80x94Oxe2x80x94 wherein aryl is phenyl, biphenyl, indenyl, naphthyl, imidazolyl, 1,2,3-triazolyl, thiophenyl, pyridyl, quinolyl, isoquinolyl, benzofuranyl, indolyl or benzimidazolyl, which aryl group is optionally substituted with halogen, nitro, cyano, hydroxy, trihalomethyl, C1-C6alkyl, R42xe2x80x94, R42xe2x80x94R14xe2x80x94, C1-C6alkyloxy, R42xe2x80x94Oxe2x80x94, R42-S(O)2xe2x80x94, R42xe2x80x94R15xe2x80x94Oxe2x80x94, R42xe2x80x94N(R16)xe2x80x94, R18xe2x80x94C(O)xe2x80x94N(R19)xe2x80x94, R40xe2x80x94C(O)xe2x80x94Oxe2x80x94R41xe2x80x94Oxe2x80x94C(O)xe2x80x94, R42xe2x80x94C(O)xe2x80x94N(R21)xe2x80x94 or R42xe2x80x94R23xe2x80x94C(O)xe2x80x94N(R24)xe2x80x94; R4 is hydrogen, R27xe2x80x94Oxe2x80x94C(O)xe2x80x94, aryl-R28xe2x80x94Oxe2x80x94C(O)xe2x80x94, R29xe2x80x94C(O)xe2x80x94Oxe2x80x94R30xe2x80x94Oxe2x80x94C(O)xe2x80x94 or aryl-R31xe2x80x94C(O)xe2x80x94Oxe2x80x94R32xe2x80x94Oxe2x80x94C(O)xe2x80x94 wherein aryl is phenyl, naphthyl or thiophenyl, which aryl group is optionally substituted with halogen, nitro, cyano, trihalomethyl, R43xe2x80x94, R43xe2x80x94R33xe2x80x94, C1-C6alkyloxy or R43xe2x80x94R34xe2x80x94Oxe2x80x94;
and wherein R5, R7, R8, R9, R10, R11, R13, R14, R15, R23, R28, R30, R31, R32, R33, R34, R39, and R41 independently are C1-C6alkylene, wherein R6, R12, R17, R18, R20, R22, R25, R27, R29, and R40 independently are C1-C6alkyl and wherein R16, R19, R21, R24, R35, R36, R37 and R38 independently are hydrogen or C1-C6alkyl, wherein R42 and R43 are independently phenyl, naphthyl or thiophenyl;
or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric form.
In another embodiment R1 and R2 are independently hydrogen, C1-C6alkyl, aryl-R5xe2x80x94, R6xe2x80x94C(O)xe2x80x94Oxe2x80x94R7xe2x80x94 or aryl-R8-C(O)xe2x80x94Oxe2x80x94R9xe2x80x94 wherein aryl is phenyl, naphthyl or thiophenyl, which aryl group is optionally substituted with halogen, nitro, trihalomethyl, C1-C6alkyl or C1-C6alkyloxy;
In another embodiment X is C(O).
In another embodiment X is S(O)2.
In another embodiment R1 and R2 are independently hydrogen, C1-C6alkyl, aryl-R5xe2x80x94, or R6xe2x80x94C(O)xe2x80x94Oxe2x80x94R7xe2x80x94, wherein aryl is phenyl, naphthyl or thiophenyl, which aryl group is optionally substituted with halogen, nitro, trihalomethyl, C1-C6alkyl or C1-C6alkyloxy.
In another embodiment R1 and R2 are independently hydrogen or C1-C6alkyl.
In another embodiment R1 and R2 are hydrogen.
In another embodiment R3 is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, aryl, aryl-R10xe2x80x94, aryl-N(R35)xe2x80x94, N(R37)(R38)xe2x80x94R39xe2x80x94, or C1-C6alkyloxy wherein aryl is phenyl, biphenyl, indenyl, naphthyl, imidazolyl, 1,2,3-triazolyl, thiophenyl, pyridyl, quinolyl, isoquinolyl, indolyl or benzimidazolyl, which aryl group is optionally substituted with halogen, nitro, cyano, hydroxy, trihalomethyl, C1-C6alkyl, R42xe2x80x94, R42xe2x80x94R14xe2x80x94, C1-C6alkyloxy, R42xe2x80x94Oxe2x80x94, R42xe2x80x94S(O)2xe2x80x94, R42xe2x80x94R15xe2x80x94Oxe2x80x94, R42xe2x80x94N(R16)xe2x80x94, R18xe2x80x94C(O)xe2x80x94N(R19)xe2x80x94, R40xe2x80x94C(O)xe2x80x94Oxe2x80x94R41xe2x80x94Oxe2x80x94C(O)xe2x80x94, R42xe2x80x94C(O)xe2x80x94N(R21)xe2x80x94 or R42xe2x80x94R23xe2x80x94C(O)xe2x80x94N(R24)xe2x80x94.
In another embodiment R3 is C1-C6alkyl, aryl, aryl-R10xe2x80x94, aryl-N(R35)xe2x80x94, or N(R37)(R38)xe2x80x94R39xe2x80x94, wherein aryl is phenyl, biphenyl, indenyl, naphthyl, imidazolyl, 1,2,3-triazolyl, thiophenyl, pyridyl, quinolyl, isoquinolyl, indolyl or benzimidazolyl, which aryl group is optionally substituted with halogen, nitro, cyano, hydroxy, trihalomethyl, C1-C6alkyl, R42xe2x80x94, R42xe2x80x94R14xe2x80x94, C1-C6alkyloxy, R42xe2x80x94Oxe2x80x94, R42xe2x80x94S(O)2xe2x80x94, R42xe2x80x94R15xe2x80x94Oxe2x80x94, R42xe2x80x94N(R16)xe2x80x94, R18xe2x80x94C(O)xe2x80x94N(R19)xe2x80x94, R40xe2x80x94C(O)xe2x80x94R41xe2x80x94Oxe2x80x94C(O)xe2x80x94, R42xe2x80x94C(O)xe2x80x94N(R21)xe2x80x94 or R42xe2x80x94R23xe2x80x94C(O)xe2x80x94N(R24)xe2x80x94.
In another embodiment R3 is is aryl, aryl-R10xe2x80x94, or aryl-N(R35)xe2x80x94, wherein aryl is phenyl, biphenyl, indenyl, naphthyl, imidazolyl, 1,2,3-triazolyl, thiophenyl, pyridyl, quinolyl, isoquinolyl, indolyl or benzimidazolyl, which aryl group is optionally substituted with halogen, nitro, cyano, hydroxy, trihalomethyl, C1-C6alkyl, R42xe2x80x94, R42xe2x80x94R14xe2x80x94, C1-C6alkyloxy, R42xe2x80x94Oxe2x80x94, R42xe2x80x94S(O)2xe2x80x94, R42xe2x80x94R15xe2x80x94Oxe2x80x94, R42xe2x80x94N(R16)xe2x80x94, R18xe2x80x94C(O)xe2x80x94N(R19)xe2x80x94, R40xe2x80x94C(O)xe2x80x94Oxe2x80x94R41xe2x80x94Oxe2x80x94C(O)xe2x80x94, R42xe2x80x94C(O)xe2x80x94N(R21)xe2x80x94 or R42xe2x80x94R23xe2x80x94C(O)xe2x80x94N(R24)xe2x80x94.
In another embodiment R3 is aryl, wherein aryl is phenyl, biphenyl, indenyl, naphthyl, imidazolyl, 1,2,3-triazolyl, thiophenyl, pyridyl, quinolyl, isoquinolyl, indolyl or benzimidazolyl, which aryl group is optionally substituted with halogen, nitro, cyano, hydroxy, trihalomethyl, C1-C6alkyl, R42xe2x80x94, R42xe2x80x94R14xe2x80x94, C1-C6alkyloxy, R42xe2x80x94Oxe2x80x94, R42xe2x80x94S(O)2xe2x80x94, R42xe2x80x94R15xe2x80x94Oxe2x80x94, R42xe2x80x94N(R16)xe2x80x94, R18xe2x80x94C(O)xe2x80x94N(R19)xe2x80x94, R40xe2x80x94C(O)xe2x80x94Oxe2x80x94R41xe2x80x94Oxe2x80x94C(O)xe2x80x94, R42xe2x80x94C(O)xe2x80x94N(R21)xe2x80x94 or R42xe2x80x94R23xe2x80x94C(O)xe2x80x94N(R24)xe2x80x94.
In another embodiment the aryl of R3 is phenyl, biphenyl, naphtyl, 1,2,3-triazolyl, indolyl or benzimidazolyl.
In another embodiment the aryl of R3 is phenyl, naphtyl, or indolyl.
In another embodiment the aryl of R3 is phenyl.
In another embodiment the aryl of R3 is substituted by halogen, hydroxy, C1-C6alkyl, R42xe2x80x94, R42xe2x80x94R14xe2x80x94, C1-C6alkyloxy, R42xe2x80x94Oxe2x80x94, R18xe2x80x94C(O)xe2x80x94N(R19)xe2x80x94, R40xe2x80x94C(O)xe2x80x94xe2x80x94Oxe2x80x94R41xe2x80x94Oxe2x80x94C(O)xe2x80x94, R42xe2x80x94C(O)xe2x80x94N(R21)xe2x80x94 or R42xe2x80x94R23xe2x80x94C(O)xe2x80x94N(R24)xe2x80x94.
In another embodiment the aryl of R3 is substituted by hydroxy, R42xe2x80x94, R42xe2x80x94R14xe2x80x94, C1-C6alkyloxy, or R42xe2x80x94Oxe2x80x94.
In another embodiment R42 is phenyl or thiophenyl.
In another embodiment R4 is hydrogen, R27xe2x80x94Oxe2x80x94C(O)xe2x80x94, or R29xe2x80x94C(O)xe2x80x94Oxe2x80x94R30xe2x80x94Oxe2x80x94C(O)xe2x80x94 wherein aryl is phenyl, naphthyl or thiophenyl, which aryl group is optionally substituted with halogen, nitro, cyano, trihalomethyl, R43xe2x80x94, R43xe2x80x94R33xe2x80x94, C1-C6alkyloxy or R43xe2x80x94R34xe2x80x94Oxe2x80x94;
In another embodiment R4 is hydrogen.
In another embodiment the aryl of R4 is phenyl.
In another embodiment the aryl of R4 is substituted by halogen, hydroxy, R43xe2x80x94, or C1-C6alkyloxy.
In a preferred embodiment, the present invention is concerned with compounds Formula 1 
wherein
X is xe2x80x94C(O)xe2x80x94;
R1 and R2 are independently hydrogen, C1-C6alkyl, aryl-R5xe2x80x94, R6xe2x80x94C(O)xe2x80x94Oxe2x80x94R7xe2x80x94 or aryl-R8xe2x80x94C(O)xe2x80x94Oxe2x80x94R9xe2x80x94 wherein aryl is phenyl, naphthyl, thiophenyl, which aryl group is optionally substituted with halogen, trihalomethyl, aryl, aryl-R14xe2x80x94, C1-C6alkyloxy or aryl-R15xe2x80x94Oxe2x80x94;
R3 is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, aryl, aryl-R10xe2x80x94, aryl-N(R35)xe2x80x94, aryl-R11xe2x80x94N(R36)xe2x80x94, N(R37)(R38)xe2x80x94R39xe2x80x94, C1-C6alkyloxy or aryl-R13xe2x80x94Oxe2x80x94 wherein aryl is phenyl, biphenyl, naphthyl, benzo[b]furanyl, 1,2,3-triazolyl, thiophenyl, pyridyl, quinolyl, isoquinolyl, or indolyl, which aryl group is optionally substituted with with halogen, hydroxy, C1-C6alkyl, R42xe2x80x94, R42xe2x80x94R14xe2x80x94, C1-C6alkyloxy, R42xe2x80x94Oxe2x80x94, R42xe2x80x94R15xe2x80x94Oxe2x80x94 R4 is hydrogen, C1-C6alkyl, R29xe2x80x94C(O)xe2x80x94Oxe2x80x94R30xe2x80x94Oxe2x80x94C(O)xe2x80x94 or aryl-R31xe2x80x94C(O)xe2x80x94Oxe2x80x94R32xe2x80x94Oxe2x80x94C(O)xe2x80x94 wherein aryl is phenyl or thiophenyl, which aryl group is optionally substituted with halogen, nitro, cyano, trihalomethyl, R43xe2x80x94, R43xe2x80x94R33xe2x80x94, C1-C6alkyloxy or R43xe2x80x94R34xe2x80x94Oxe2x80x94;
or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric form.
More preferred compounds of the invention are compounds of Formula 1
wherein
X is xe2x80x94C(O)xe2x80x94;
R1 and R2 are independently hydrogen or C1-C6alkyl;
R3 is C1-C6alkyl, aryl-R10, aryl, aryl-N(R35)xe2x80x94, or aryl-R13xe2x80x94Oxe2x80x94 wherein aryl is phenyl, biphenyl, naphthyl, benzo[b]furanyl, 1,2,3-triazolyl, thiophenyl, pyridyl, quinolyl, isoquinolyl, or indolyl, which aryl group is optionally substituted with halogen, hydroxy, C1-C6alkyl, R42xe2x80x94, R42xe2x80x94R14xe2x80x94, C1-C6alkyloxy, R42xe2x80x94Oxe2x80x94, R42xe2x80x94R15xe2x80x94Oxe2x80x94;
R4 is hydrogen, R29xe2x80x94C(O)xe2x80x94Oxe2x80x94R30xe2x80x94Oxe2x80x94C(O)xe2x80x94 or aryl-R31xe2x80x94C(O)xe2x80x94Oxe2x80x94R32xe2x80x94Oxe2x80x94C(O)xe2x80x94 wherein aryl is phenyl or thiophenyl, which aryl group is optionally substituted with halogen, nitro, cyano, trihalomethyl, R43xe2x80x94, R43R33xe2x80x94, C1-C6alkyloxy or R43xe2x80x94R34xe2x80x94Oxe2x80x94;
or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric form.
Even more preferred compounds of the invention are compounds of Formula 1 
wherein
X is xe2x80x94C(O)xe2x80x94;
R1, R2 and R4 are hydrogen;
R3 is C1-C6alkyl, aryl, aryl-R10xe2x80x94, aryl-N(R35)xe2x80x94, or aryl-R13xe2x80x94Oxe2x80x94 wherein aryl is phenyl, biphenyl, naphthyl, 1,2,3-triazolyl, thiophenyl, pyridyl, quinolyl, isoquinolyl, or indolyl, which aryl group is optionally substituted with halogen, hydroxy, C1-C6alkyl, R42xe2x80x94, R42-R14xe2x80x94, C1-C6alkyloxy, R42xe2x80x94O, R42xe2x80x94R15xe2x80x94Oxe2x80x94;
or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric form.
The following compounds are preferred:
7-(Benzoylamino-methyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
7-(((1H-Indole-3-carbonyl)amino)methyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
7-(((5-Hydroxy-1H-indole-2-carbonyl)amino)methyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pridine-3-carboxylic acid;
7-(((5-Methyl-2-phenyl-2H-[1,2,3]triazole-4-carbonyl)amino)methyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
7-((4-Ethoxy-2-hydroxy-benzoylamino)methyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyidine-3-carboxylic acid;
7-((4-Benzoylamino-benzoylamino)methyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
7-(((Biphenyl-4-carbonyl)amino)methyl)-2-(oxalyl-amino)-4,5,6, 7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
7-(((5-Methoxy-1H-indole-2-carbonyl)amino)methyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
7-((3-Biphenyl-4-yl-propionylamino)methyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]-pyridine-3-carboxylic acid;
7-(((1H-Indole-2-carbonyl)amino)methyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
7-((4-Benzyl-benzoylamino)methyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
7-(((Naphthalene-1-carbonyl)amino)methyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
7-((3-Naphthalen-2-yl-propionylamino)methyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
7-(((2-Hydroxy-naphthalene-1-carbonyl)amino)methyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
7-(((2-Ethoxy-naphthalene-1-carbonyl)amino)methyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
7-(S)-((4-Benzenesulfonyl-benzoylamino)methyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
7-(S)-(((Naphthalene-2-carbonyl)amino)methyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2, 3-c]pyridine-3-carboxylic acid;
2-(Oxalyl-amino)-7-(S)-((3-phenoxy-benzoylamino)methyl]-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
2-(Oxalyl-amino)-7-(S)-((4-phenyl-butyrylamino)methyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
7-(S)-(((7-Ethoxy-benzofuran-2-carbonyl)amino)methyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
7-(S)-(((4xe2x80x2-Hydroxy-biphenyl-4-carbonyl)amino)methyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
7-(S)-((4-Acetylamino-benzenesulfonylamino)methyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
7-(S)-(((5-Methoxy-benzofuran-2-carbonyl)amino)methyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
7-(S)-(((3H-Benzoimidazole-5-carbonyl)amino)methyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
7-(S)-(((5-Hydroxy-1H-indole-2-carbonyl)amino)methyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
7-(R)-(((5-Hydroxy-1H-indole-2-carbonyl)amino)methyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
7-(R)-(((1-Benzyl-1H-indole-3-carbonyl)amino)methyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
2-(Oxalyl-amino)-7-(S)-((4-phenoxy-benzylamino)methyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
2-(Oxalyl-amino)-7-(S)-(3-(4-phenoxy-phenyl)ureidomethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
7-(((1-Benzyl-1H-indole-3-carbonyl)amino)methyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
7-(((1-Benzyl-1H-indole-3-carbonyl)amino)methyl)-6-methyl-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
7-(Acetylamino-methyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
7-((5-Amino-5-methyl-hexanoylamino)methyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
7-(S)-(((5-Fluoro-1H-indole-2-carbonyl)amino)methyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
7-(S)-(((5-Hydroxy-1H-indole-2-carbonyl)amino)methyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyridine-3,6-dicarboxylic acid 6-acetoxymethyl ester;
7-(S)-(((5-Acetoxymethoxycarbonyloxy-1H-indole-2-carbonyl)amino)methyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyridine-3,6-dicarboxylic acid 6-acetoxymethyl ester;
2-(Oxalyl-amino)-7-(S)-((([1,1xe2x80x2;3xe2x80x2,1xe2x80x3]terphenyl-4-carbonyl)aminomethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
7-(S)-(((1H-Indole-2-carbonyl)amino)methyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
2-(Ethoxyoxalyl-amino)-7-(((5-hydroxy-1H-indole-2-carbonyl)amino)methyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid;
2-(Ethoxyoxalyl-amino)-7-(((5-hydroxy-1H-indole-2-carbonyl)amino)methyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid ethyl ester;
2-((2,2-Dimethyl-propoxyoxalyl)amino)-7-(((5-hydroxy-1H-indole-2-carbonyl)-amino)methyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid ethyl ester;
7-(((5-Hydroxy-1H-indole-2-carbonyl)amino)methyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyridine-3-carboxylic acid ethyl ester;
7-(((5-Hydroxy-1H-indole-2-carbonyl)amino)methyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyridine-3,6-dicarboxylic acid 6-ethyl ester;
or a pharmaceutically acceptable salt thereof.
In another embodiment R1 is hydrogen.
In another embodiment R2 is hydrogen.
In another embodiment R1 and R2 are hydrogen.
In another embodiment R4 is hydrogen.
In another embodiment R1, R2 and R4 are hydrogen.
In another embodiment R4 is R29xe2x80x94C(O)xe2x80x94Oxe2x80x94R30xe2x80x94Oxe2x80x94C(O)xe2x80x94; wherein R29 and R30 are as defined in claim 1.
In another embodiment R4 is aryl-R31xe2x80x94C(O)xe2x80x94Oxe2x80x94R32xe2x80x94Oxe2x80x94C(O)xe2x80x94, wherein R31 and R32 are as defined in claim 1 and the aryl group is optionally substituted as defined in claim 1.
In another embodiment R3 is aryl as defined in claim 1.
In another embodiment the aryl of R3 group is 2-hydroxy-phenyl.
In another embodiment the aryl group of R3 is 4-ethoxy-2-hydroxy-phenyl and X is xe2x80x94C(O)xe2x80x94.
In another embodiment the aryl group of R3 is 4-benzoyl-amino-phenyl and X is xe2x80x94C(O)xe2x80x94.
In another embodiment the aryl group of R3 is 4-biphenyl and X is xe2x80x94C(O)xe2x80x94.
In another embodiment the aryl group of R3 is 3-phenoxy-phenyl and X is xe2x80x94C(O)xe2x80x94.
In another embodiment R4 is R29xe2x80x94C(O)xe2x80x94Qxe2x80x94R30xe2x80x94Oxe2x80x94C(O)xe2x80x94; wherein R29 and R30 are as defined in claim 1.
In another embodiment the aryl group of R3 4-benzenesulfonyl-phenyl and X is xe2x80x94C(O)xe2x80x94.
In another embodiment the aryl group of R3 is naphthyl; wherein the naphthyl group is optionally substituted as defined in claim 1.
In another embodiment the aryl group of R3 is 2-hydroxy-naphthyl and X is xe2x80x94C(O)xe2x80x94.
In another embodiment the aryl group of R3 is 2-ethoxy-naphthyl and X is xe2x80x94C(O)xe2x80x94.
In another embodiment the aryl group of R3 is 1H-indolyl; where in the 1H-indolyl group is optionally substituted as defined in claim 1.
In another embodiment the aryl group of R3 is 1H-indol-2-y and X is xe2x80x94C(O)xe2x80x94.
In another embodiment the aryl group of R3 is 5-methoxy-1H-indol-2-yl and X is xe2x80x94C(O)xe2x80x94.
In another embodiment the aryl group of R3 is 5-hydroxy-1H-indol-2-yl and X is xe2x80x94C(O)xe2x80x94.
In another embodiment the aryl group of R3 is benzimidazolyl; wherein the benzimidazolyl group is optionally substituted as defined in claim 1.
In another embodiment the aryl group of R3 is 5-methoxy-benzimidazol-2-yl.
In another embodiment the aryl group of R3 is 7-ethoxy-benzimidazol-2-yl.
In another embodiment the aryl group of R3 is 1,2,3-triazolyl; wherein the 1,2,3-triazolyl group is optionally substituted as defined in claim 1.
In another embodiment the aryl group of R3 is 5-methyl-2-phenyl-2H-[1,2,3]triazolyl and X is xe2x80x94C(O)xe2x80x94.
In another embodiment the aryl group of R3 is 4-acetylamino-phenyl and X is xe2x80x94SO2xe2x80x94.
In another embodiment R3 is aryl-R13xe2x80x94Oxe2x80x94; wherein R13 is as defined in claim 1 and the aryl group is optionally substituted as defined in claim 1.
In another embodiment the aryl group of R3 is phenyl.
In another embodiment R3 is aryl-N(R35); wherein R35 is as defined in claim 1 and the aryl group is optionally substituted as defined in claim 1.
In another embodiment the aryl group of R3 is 4-phenoxyphenyl and X is xe2x80x94C(O)xe2x80x94.
In another embodiment R3 is aryl-R10xe2x80x94; wherein the aryl group is optionally substituted as defined in claim 1.
In another embodiment the aryl group of R3 is phenyl and X is xe2x80x94C(O)xe2x80x94.
In another embodiment the aryl group of R3 is biphenyl and X is xe2x80x94C(O)xe2x80x94.
In another embodiment the aryl group of R3 is naphthyl and X is xe2x80x94C(O)xe2x80x94.
In another embodiment the compounds of the invention act as inhibitors of Protein Tyrosine Phosphatases.
Another aspect of the invention is a pharmaceutical composition comprising a compound of the invention or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric form together with one or more pharmaceutically acceptable carriers or diluents.
Another aspect of the invention is a pharmaceutical composition suitable for treating type 1 diabetes, type 2 diabetes, impaired glucose tolerance, insulin resistance or obesity comprising a compound of the invention or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric form together with one or more pharmaceutically acceptable carriers or diluents.
Another aspect of the invention is a pharmaceutical composition suitable for treating immune dysfunctions including autoimmunity, diseases with dysfunctions of the coagulation system, allergic diseases, osteoporosis, proliferative disorders including cancer and psoriasis, diseases with decreased or increased synthesis or effects of growth hormone, diseases with decreased or increased synthesis of hormones or cytokines that regulate the release of/or response to growth hormone, diseases of the brain including Alzheimer""s disease and schizophrenia, and infectious diseases comprising a compound of the invention or a pharmaceutical acceptable salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric form together with one or more pharmaceutically acceptable carriers or diluents.
Another aspect of the invention is a pharmaceutical composition of the invention in the form of an oral dosage unit or parenteral dosage unit.
Another aspect of the invention is a pharmaceutical composition of the invention wherein said compound is administered as a dose in a range from about 0.05 to 1000 mg, preferably from about 0.1 to 500 mg and especially in the range from 50 to 200 mg per day.
Another aspect of the invention is a compound of the invention or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric form for therapeutical use.
Another aspect of the invention is a compound of the invention or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric form for therapeutical use in the treatment or preventing of type 1 diabetes, type 2 diabetes, impaired glucose tolerance, insulin resistance or obesity.
Another aspect of the invention is a compound of the invention or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric form for therapeutical use in the treatment or preventing of immune dysfunctions including autoimmunity, diseases with dysfunctions of the coagulation system, allergic diseases, osteoporosis, proliferative disorders including cancer and psoriasis, diseases with decreased or increased synthesis or effects of growth hormone, diseases with decreased or increased synthesis of hormones or cytokines that regulate the release of/or response to growth hormone, diseases of the brain including Alzheimer""s disease and schizophrenia, and infectious diseases.
Another aspect of the invention is the use of a compound of the invention or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric form as a medicament.
Another aspect of the invention is the use of a compound of the invention for preparing a medicament.
Another aspect of the invention is the use of a compound of the invention or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric form for the preparation of a medicament suitable for the treatment or preventing of type 1 diabetes, type 2 diabetes, impaired glucose tolerance, insulin resistance or obesity.
Another aspect of the invention is the use of a compound of the invention or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric form for the preparation of a medicament suitable for the treatment or preventing of immune dysfunctions including autoimmunity, diseases with dysfunctions of the coagulation system, allergic diseases, osteoporosis, proliferative disorders including cancer and psoriasis, diseases with decreased or increased synthesis or effects of growth hormone, diseases with decreased or increased synthesis of hormones or cytokines that regulate the release of/or response to growth hormone, diseases of the brain including Alzheimer""s disease and schizophrenia, and infectious diseases.
Another aspect of the invention is a method of treating type 1 diabetes, type 2 diabetes, impaired glucose tolerance, insulin resistance or obesity comprising administering to a subject in need thereof an effective amount of a compound of the invention to said subject.
Another aspect of the invention is a method of treating immune dysfunctions including autoimmunity, diseases with dysfunctions of the coagulation system, allergic diseases, osteoporosis, proliferative disorders including cancer and psoriasis, diseases with decreased or increased synthesis or effects of growth hormone, diseases with decreased or increased synthesis of hormones or cytokines that regulate the release of/or response to growth hormone, diseases of the brain including Alzheimer""s disease and schizophrenia, and infectious diseases comprising administering to a subject in need thereof an effective amount of a compound of the invention to said subject.
Another aspect of the invention is a process for the manufacture of a medicament, particular to be used in the treatment or prevention of type 1 diabetes, type 2 diabetes, impaired glucose tolerance, insulin resistance or obesity which process comprising bringing a compound of the invention or a pharmaceutically acceptable salt thereof into a galenic dosage form.
Another aspect of the invention is a process for the manufacture of a medicament, particular to be used in the treatment or prevention of immune dysfunctions including autoimmunity, diseases with dysfunctions of the coagulation system, allergic diseases, osteoporosis, proliferative disorders including cancer and psoriasis, diseases with decreased or increased synthesis or effects of growth hormone, diseases with decreased or increased synthesis of hormones or cytokines that regulate the release of/or response to growth hormone, diseases of the brain including Alzheimer""s disease and schizophrenia, and infectious diseases which process comprising bringing a compound of the invention or a pharmaceutically acceptable salt thereof into a galenic dosage form.
Another aspect of the invention is a method for preparing a compound of Formula 1, characterized in 
a) NCxe2x80x94CH2xe2x80x94COOR1, sulphur, morpholine or triethylamine, EtOH; b) R3xe2x80x94Oxe2x80x94C(O)xe2x80x94C(O)-imidazol-1-yl, THF; c) 25% TFA/CH2Cl2; wherein X, R1, R2, R3, and R4 are defined above.
The reaction step a) in Method A gives a mixture of regioisomers which can be separated by use of column chromatography known to those skilled in the art. 
a) By allowing an activated carboxylic acid or sulfonic acid (I); wherein X is xe2x80x94C(CO)xe2x80x94 and W is xe2x80x94OH, xe2x80x94OSO2Me, halogen, R4COOxe2x80x94 or X is xe2x80x94SO2xe2x80x94 and W is chloride, a substituted 5-aminomethyl-tetrahydro-thieno[2,3-c]pyridine (II) to react under conditions known to those skilled in the art which favour amide or sulfonamide bond formation followed by b) R2xe2x80x94Oxe2x80x94C(O)xe2x80x94C(O)-imidazol-1-yl, THF and c) 25% TFA/CH2Cl2; to yield (III) wherein R1, R2, R3, and R4 are defined above.
Pharmacological Methods
The compounds are evaluated for biological activity with a truncated form of PTP1 B (corresponding to the first 321 amino acids), which was expressed in E. coli and purified to apparent homogeneity using published procedures well-known to those skilled in the art. The enzyme reactions are carried out using standard conditions essentially as described by Burke et al. (Biochemistry 35; 15989-15996 (1996)). The assay conditions are as follows. Appropriate concentrations of the compounds of the invention are added to the reaction mixtures containing different concentrations of the substrate, p-nitrophenyl phosphate (range: 0.16 to 10 mMxe2x80x94final assay concentration). The buffer used was 100 mM sodium acetate pH 5.5, 50 mM sodium chloride, 0.1% (w/v) bovine serum albumin and 5 mM dithiothreitol (total volume 100 ml). The reaction was started by addition of the enzyme and carried out in microtiter plates at 25xc2x0 C. for 60 minutes. The reactions are stopped by addition of NaOH. The enzyme activity was determined by measurement of the absorbance at 405 nm with appropriate corrections for absorbance at 405 nm of the compounds and p-nitrophenyl phosphate. The data are analyzed using nonlinear regression fit to classical Michaelis Menten enzyme kinetic models. Inhibition is expressed as Ki values in xcexcM. The results of representative experiments are shown in Table 1.
The Synthesis of the Compounds
In accordance with one aspect of the invention, the compounds of the invention are prepared as illustrated in the following reaction scheme: 
a) NCxe2x80x94CH2xe2x80x94COOR1, sulphur, morpholine or triethylamine, EtOH; b) R3xe2x80x94Oxe2x80x94C(O)xe2x80x94C(O)-imidazol-1-yl, THF; c) 25% TFA/CH2Cl2; wherein X, R1, R2, R3, and R4 are defined above.
The reaction step a) in Method A gives a mixture of regioisomers which can be separated by use of column chromatography known to those skilled in the art. 
a) By allowing an activated carboxylic acid or sulfonic acid (I); wherein X is xe2x80x94C(CO)xe2x80x94 and W is xe2x80x94OH, xe2x80x94OSO2Me, halogen, R4COOxe2x80x94 or X is xe2x80x94SO2xe2x80x94 and W is chloride, a substituted 5-aminomethyl-tetrahydro-thieno[2,3-c]pyridine (II) to react under conditions known to those skilled in the art which favour amide or sulfon amide bond formation followed by b) R2xe2x80x94Oxe2x80x94C(O)xe2x80x94C(O)-imidazol-1-yl, THF and c) 25% TFA/CH2Cl2; to yield (III) wherein R1, R2, R3, and R4 are defined above.
Pharmacological Preparations
For the above indications the dosage will vary depending on the compound of the invention employed, on the mode of administration and on the therapy desired. However, in general, satisfactory results are obtained with a dosage of from about 0.5 mg to about 1000 mg, preferably from about 1 mg to about 500 mg of compounds of the invention, conveniently given from 1 to 5 times daily, optionally in sustained release form. Usually, dosage forms suitable for oral administration comprise from about 0.5 mg to about 1000 mg, preferably from about 1 mg to about 500 mg of the compounds of the invention admixed with a pharmaceutical carrier or diluent.
The compounds of the invention may be administered in a pharmaceutically acceptable acid addition salt form or where possible as a metal or a C1-6-alkylammonium salt. Such salt forms exhibit approximately the same order of activity as the free acid forms.
This invention also relates to pharmaceutical compositions comprising a compound of the invention or a pharmaceutically acceptable salt thereof and, usually, such compositions also contain a pharmaceutical carrier or diluent. The compositions containing the compounds of this invention may be prepared by conventional techniques and appear in conventional forms, for example capsules, tablets, solutions or suspensions.
The pharmaceutical carrier employed may be a conventional solid or liquid carrier. Examples of solid carriers are lactose, terra alba, sucrose, talc, gelatine, agar, pectin, acacia, magnesium stearate and stearic acid. Examples of liquid carriers are syrup, peanut oil, olive oil and water.
Similarly, the carrier or diluent may include any time delay material known to the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
If a solid carrier for oral administration is used, the preparation can be tabletted; placed in a hard gelatine capsule in powder or pellet form or it can be in the form of a troche or lozenge. The amount of solid carrier will vary widely but will usually be from about 25 mg to about 1 g. If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.
Generally, the compounds of this invention are dispensed in unit dosage form comprising 10-200 mg of active ingredient in or together with a pharmaceutically acceptable carrier per unit dosage.
The dosage of the compounds according to this invention is 1-500 mg/day, e.g. about 100 mg per dose, when administered to patients, e.g. humans, as a drug.
A typical tablet that may be prepared by conventional tabletting techniques contains
The route of administration may be any route, which effectively transports the active, compound to the appropriate or desired site of action, such as oral or parenteral e.g. rectal, transdermal, subcutaneous, intranasal, intramuscular, topical, intravenous, intraurethral, ophthalmic solution or an ointment, the oral route being preferred.
A number of procedures, well known to those skilled in the art, may be used to verify that the attached chemical groups have been removed or that the cyclic compound has been hydrolyzed after uptake in cells or mammals. An example, which is not intended in any way to limit the scope of the invention, is given in the following. A mammalian cell line, which can be obtained from the American Tissue Type Collection or other similar governmental or commercial sources, is incubated with said modified compound. After incubation at conditions well known to those skilled in the art, the cells are washed appropriately, lysed and the lysate is isolated. Appropriate controls, well known to those skilled in the art, must be included. A number of different procedures, well known to those skilled in the art, may in turn be used to extract and purify said compound from said lysate. Said compound may or may not retain the attached chemical group or said cyclic compound may or may not have been hydrolyzed. Similarly, a number of different proceduresxe2x80x94well known to those skilled in the artxe2x80x94may be used to structurally and chemically characterize said purified compound. Since said purified compound has been isolated from said cell lysate and hence has been taken up by said cell line, a comparison of said structurally and chemically characterized compound with that of the original unmodified compound (i.e. without said attached chemical group or said non-cyclic compound) will immediately provide those skilled in the art information on whether the attached chemical group as been removed in the cell or if the cyclic compound has been hydrolyzed. As a further analysis, said purified compound may be subjected to enzyme kinetic analysis as described in detail in the present invention. If the kinetic profile is similar to that of the original compound without said attached chemical group, but different from said modified compound, this confirms that said chemical group has been removed or said cyclic compounds has been hydrolyzed. Similar techniques may be used to analyze compounds of the invention in whole animals and mammals.